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NEUROPATHY

Commonest complication associated with diabetes.

Clinical Classification of DIABETIC NEUROPATHY

Somatic Neuropathy

GRADUAL ONSET
Type Type
Distal symmetrical polyneuropathy Chronic symmetrical symptoms affecting peripheral nerves with the longest nerves usually affected first; Sensory and motor functions affected in varying degrees, but may be predominantly sensory. Often associated with autonomic dysfunction;

Signs and symptoms varies commonly presents with tingling or numbness ( with or without pain) pain usually bilateral beginning in the feet, spreading proximally in stocking like fashion; Later the upper extremities develop similar manifestations and progress upwards in a glove like manner; Loss of balance, especially with the eyes closed, and painless injuries due to loss of sensation are common.
ACUTE ONSET
Type Signs and Symptoms
Painful symmetric polyneuropathy As above but with an acute onset and associated with significant burning, stabbing, crushing, aching, or cramplike symptoms, with increased severity at night;
Mononeuropathy multiplex An individual nerve can be affected, such as the peroneal nerve, resulting in footdrop, median neuropathy of the wrist, ulnar neuropathy of the elbow

Symptoms usually comprise pain, tingling, numbnessand wasting and weakness;

This might be in the form of solitary nerve involvement or in combination-mononeuropathy or mononeuropathy multiplex.
Cranial mononeuropathy CN III, IV, and VI disease manifests as acute headache or eye pain followed by diplopia developing over a few hours; Muscle weakness is typically in the distribution of a single nerve, and pupillary light reflexes are usually spared.

Facial neuropathy (CN VII) manifests as acute or subacute facial weakness (taste is not normally involved) and can be recurrent or bilateral.
Diabetic radiculoplexopathy Also known as Proximal motor neuropathy (amyotrophy) Starts as sudden, severe, unilateral pain usually in the lower back, hips, and thighs and may occur in the shoulder/neck;

Weakness and atrophy usually develop over a brief time. Reflexes in the affected limb may be depressed. Numbness and paresthesias may occur;

Accompanied with depression and significant ooss of appetite with significant weight loss in more than 50% of the patients;

Usually seen on older people;
Diabetic radiculopathy and Diabetic polyradiculopathy Burning, stabbing, boring, belt-like, or deep aching pain in the territory of a nerve root; usually begins unilaterally, may become bilateral. Numbness is most prominent in distal distribution of nerve roots. Skin hypersensitivity may occur;

Weakness presents in the distribution of the affected nerve root;

Coexisting diabetic distal symmetrical polyneuropathy often is present;

Single or more commonly multiple spinal roots are involved
Diabetic neuropathic cachexia Presents with severe weight loss usually in older subjects often not diagnosed as having diabetes;

Followed by severe pain and signs and symptoms of autonomic neuropathy;

Muscle weakness is rare;


Autonomic Neuropathy (AN)

Clinical Manifestations of Autonomic Neuropathy (AN)




DIAGNOSIS

Screening

A) Careful History : Questions related to the sensory (tingling, numbness, anaesthesia, parasthesias, inco-ordination), motor (wasting, weakness, nocturnal muscle cramps) and autonomic (gastrointestinal and bladder symptoms, sexual dysfunction, postural light-headedness) nervous systems, etc.

B) Tests for Peripheral Sensation : Check for touch, pain (pinprick) and vibration thresholds (calibrated tuning fork).

Although tests like nerve conduction studies and EMG can be done, in clinical terms, the most simple test known as the Monofilament test. This allows a very simple but clinically important study of the sensation in the feet which, if often and correctly done can help in avoiding the most dreaded of complications such as foot injuries and infections.

For a note on the use of the Monofilament Test see appendix 9a

C) Motor Involvement : Check for muscle weakness and wasting.

D) Reflexes

E) Detecting Autonomic Neuropathy

Simple clinical tests for Detecting autonomic neuropathy
Tests for autonomic neuropathy Normal response Abnormal response
Resting heart rate     >100/minute
Heart rate response to standing Measure R-R interval at beats 15 and 30 after the patient stands   A 30:15 ratio of less than 1.03 is abnormal
Systolic blood pressure changes on standing Measure systolic blood pressure lying down then standing. Decrease < 10 mm Hg Decrease > 30 mm Hg
Heart rate response to deep breathing Measure heart rate response to deep breathing Increase rate > 15 beats /min Increase < 10 beats /min

Differential Diagnosis

Diabetic neuropathy has a plethora of presentations that must be differentiated from other disorders that may have similar features such as alcoholic neuropathy, B12 deficinecy etc.

As many as 10-20 % of people with diabetes may have an alternative cause for the neuropathy. If motor deficit or proprioceptive involvement predominates, it is important to consider nondiabetic causes of neuropathy

For a partial list of common conditions in the differential diagnosis of diabetic peripheral neuropathy, see Appendix 9b


MANAGEMENT

Somatic Neuropathy

Glycemic Control

Tight and stable glycemic control is probably the only treatment approach that may provide symptomatic relief and slow the progression of the diabetic neuropathy. Fluctuations of in the blood glucose levels can aggravate and induce neuropathic pain rather than the level of hyperglycemia. Some suggest that the stability rather than the actual level of glycemic control may be more important in relieving neuropathic pain.

MANAGEMENT

Specific Therapy

Control of the Hyperglycemia


Whilst this may not always ensure that diabetic neuropathy will not occur or progress, there is adequate evidence to show that optimal management of the blood glucose levels is of significant importance. More over there is some evidence that as much as the plasma glucose levels, wide fluctuations in these levels is also very detrimental to the nerves.

Aldose reductase inhibitors, a-Lipoic acid, ?-Linolenic acid have been used with varying results, especially the last two. Aldose reductase inhibitors did not live up to their supposed potential to treat diabetic neuropathy. Injections of B1, B6, and B12 are routinely used by many doctors when faced with a patient with diabetic neuropathy. Unless there is manifest evidence of the deficiency of these vitamins in the patient, the injections would be of use only as a placebo.


Painful Neuropathy


One of the most difficult conditions to manage in patients with diabetic peripheral neuropathy is the painful neuropathies. At the same time, many newer drugs are now available which do tend to improve our ability to give relief in such cases, provided that they are used with care.


Commonly used drugs to treat painful neuropathy

Commonly used drugs to treat painful neuropathy
Category Drugs Side Effects
 
Tricyclic Antidepressants Nortriptyline, start at10-25 mg at bedtime andtitrate every 3-4 days to maximum of 75-150 mg/day Side effects common to all tricyclic antidepressants include include dry mouth, drowsiness, diziness, constipation, urinary retneion, blurred vision, confusion, disorientation, increased appetite, tachycardia
  Amitryptiline, start at10-25 mg at bedtime andtitrate every 3-4 days to to maximum of 75-150 mg/day
Anticonvulsants Carbamazepine,400 mg po tid Requires titration; side effectsinclude ataxia, dizziness, somnolence, dyspepsia, nausea, vomiting, blurred vision, confusion, weakness, fatigue, nystagmus, aplastic anemia
  Gabapentin, Usual starting dose is 300mg at bedtime and can be titrated upwards every week to a maximum of 1800-3000mg/day in three divided doses depending on the tolerability and efficacy. Elderly patients should start at much lower doses. Requires titration; side effectsinclude ataxia, diplopia, blurred vision, tremors, dyspepsia, nausea, vomiting, constipation, fatigue, leukopenia
  Pregabalin, Dosing can begin at 150mg/day in divided doses and may be increased to 300/day within a week depending on the tolerability and efficacy. Dose should be reduced in patients with renal dysfunction; Requires titration; side effects similar to gabapentin but relatively better tolerated;
  Lamotrigine, start at 50mg/day increase by 100mg biweekly till 200-600mg.day is reached depending on the tolerability and efficacy Requires titration; side effectsinclude ataxia, dizziness, somnolence, diplopia, blurred vision, nystagmus, headache, dyspepsia, nausea, vomiting, constipation, fatigue, rash, impaired memory
Nonopioid analgesics Tramadol, start at 50mg daily and titrate upwards by 50mg weekly till a dose of 200-400mg is reached depending on the tolerability and efficacy Nausea, constipation, somnolence, headache, dry mouth, seizures, confusion, tremors, anorexia, urinary retention
Opioids Oxycodone, start with 20mg every 12 hours and increase gradually by 10mg/ week till 40-160/ day in divided doses is reached depending on the tolerability and efficacy Dizziness, somnolence, diplopia, headache, dyspepsia, nausea, vomiting, constipation, dry mouth, sweating, low blood pressure
Local therapy 5% lidocaine patch applied to painful areas; apply for 12 hours, off for 12 hours, upto 3-4 patches maximum at a time Localised erythema, burning, swelling
  Isosorbide dinitrate spray.  


Pharmacologic treatment of autonomic neuropathy

  Drug Dosage Common Side effects
Orthostatic hypotension 9 alpha flouro hydrocortisone, mineralocorticoid 0.5-2 mg/day Congestive heart failure, hypertension
  Clonidine, alpha2 adrenergic agonist 0,1-0,5 mg, at bedtime Hypotension, sedation, dry mouth
Gastroparesis diabeticorum Metoclopramide, D2 -receptor antagonist 5-20 mg 30-60 minutes before meals and at bedtime Galactorrhea, extrapyramidal symptoms drowsiness, restlessness, diarrhea, weakness
  Domperidon, D2-receptor antagonist 25 mg, 3 times/day Galactorrhea
  Erythromycin, motilin receptor agonist 250 mg, 30 minutes before meals Abdominal cramp, nausea, diarrhoea, rash
  Levosulpide, D2-receptor antagonist 25 mg, 3 times/day Galactorrhea
Diabetic diarrhea Metronidazole, broad spectrum antibiotics 250 mg, 3 times/day, minimum 3 weeks Orthostatic hypotension
  Clonidine, alpha 2 adrenergic agonist 0.1 mg, 2-3 times/day Hypotension, sedation, dry mouth
  Cholestyramine, bile acid sequestrant 4 g, 1-6 times/day    
  Loperamide, opiate-receptor agonist 2 mg, four times/day Toxic megacolon
Cystopathy Bethanechol, acetylcholine receptor agonist 10 mg, 4 times/day    
  Doxazosin, alpha1 adrenergic antagonist 1-2 mg, 2-3 times/day Hypotension, headache, palpitation
Erectile dysfunction Sildenafil 25-100mgTadlafil 5-20mgVardenafil 2.5-20mg

GMP type-5 phosphodiesterase inhibitor
Lowest possible dose

Patients over the age of 65 years, or those with significant liver disease or renal dysfunction and those who are taking CYP3A4 inhibitors (eg, indinavir, erythromycin, ketoconazole) should begin treatment at lower doses.
Nitrates in any form are contraindicated. Caution should also be used with other antihypertensive agents in order to avoid hypotension. Patients taking alpha blockers should avoid vardenafil and tadalafil. Lower dosages of sildenafil (25 mg) are preferable if these two types of drugs have to be combined. Headache, flushing, nasal congestion, dyspepsia, muscoloskeletal pain, blurred vision;


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